Chronic inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, involve therapeutical problems which have still to be satisfactorily solved. The use of the medicaments available to date, such as aminosalicylates and pro-drugs thereof, steroids, immunosuppressive agents, is often restricted by the important side effects involved as well as by the sometime insufficient effectiveness.
Safer, more effective medicaments than those presently available are therefore particularly needed.
Recently, the use of heparin has been suggested in the IBD parenteral treatment: in fact, although IBD etiology has still to be clarified, its pathogenesis is somewhat clearer, and this can account for the use of heparin in this disease.
In particular, the thrombophilic state frequently observed in ulcerative colitis favours intravasal district coagulation, which is confirmed by the presence of sub-mucosal microthrombosis and by vasculytic phenomena on the mesenteral vessels; furthermore, important inflammatory conditions are always present, which can be related with an alteration of both the immune system and the Th1/Th2 balance, which are mediated by interleukins (IL-1), TNF and numerous other pro-inflammatory cytokines.
All these considerations suggest the presence of vascular damage associated with, or consequent to, inflammatory conditions on an immune base, in the pathogenesis of ulcerative colitis.
Clinical studies have confirmed the therapeutical activity of heparin administered parenterally, usually through subcutaneous injection, in the treatment of IBD (Aliment. Pharmacol. Ther. 1997; 11:1037-1040; Inflammatory Bowel Diseases, 1997; 3(2): 87-94; Gastroenterology, 1996; 110:A872; Gastroenterology, 1996; 110. A 900; Gastroenterology, 1996; 110. A908, Gut, 1995; 137(S2)F194; Am. J. Gastroenterol. 1995; 90:220-223).
In these clinical studies, heparin was always administered intravenously or subcutaneously, namely through the conventional administration routes of choice for heparins and other glycosaminoglycan derivatives, which usually are not absorbed orally. Studies have been carried out for alternative administration routes to the injective one, such as the oral administration, which is by far suitable for self-medication for use in the antithrombotic therapy. However, heparin and low molecular weight derivatives thereof, when administered orally, are absorbed in insufficient amounts to attain an effective concentration and usually only in the first tract of intestine.
On the other hand, considering the chronic nature of IBD, the oral administration would be much preferable, as the treatment is usually long-term.
Formulations studied to increase heparin absorption in the gastrointestinal tract are described in WO-A-01/34114 and WO-A-00/48589.